Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: part I

This is the first of a series of reviews of the controversy that swirled around the “lipid hypothesis” of atherosclerosis for so many years. Today, in the era of the statins, there is no longer any doubt about the value of decreasing blood cholesterol levels. In fact, “the lower the better” is the position of many clinicians. However, getting to this point has been a long uphill battle marked by heated debate and sometimes violent disagreement.The history of this controversy is worth telling for its own sake and because remembering it may help us avoid similar mistakes in the future. This is the first of a series of reviews of the controversy that swirled around the “lipid hypothesis” of atherosclerosis for so many years. Today, in the era of the statins, there is no longer any doubt about the value of decreasing blood cholesterol levels. In fact, “the lower the better” is the position of many clinicians. However, getting to this point has been a long uphill battle marked by heated debate and sometimes violent disagreement. The history of this controversy is worth telling for its own sake and because remembering it may help us avoid similar mistakes in the future. The history of science is studded with controversies, and this is especially true of medical science. Certainly, some measure of skepticism is appropriate. New hypotheses need to be critically tested and new treatments need to be carefully evaluated for efficacy and safety. Therefore, some degree of conservatism is a virtue when it prevents the adoption of inadequately tested new treatments, such as the use of thalidomide in pregnant women. On the other hand, an overly cautious approach and an exaggerated skepticism can delay the introduction of therapies that might save lives. The hypothesis that high blood cholesterol levels contribute causally to atherosclerosis and coronary heart disease (the “lipid hypothesis”) was for too many years a victim of exaggerated skepticism. Today, when “good cholesterol” and “bad cholesterol” are the stuff of cocktail hour chatter, it may come as a surprise that dyslipidemia was not always accepted as a significant factor in atherosclerosis and coronary heart disease. Yet in 1946, Peters and VanSlyke, in their classic textbook, Quantitative Clinical Chemistry, summarized their view of the evidence this way: “although there can be no doubt that deposits of lipids, especially cholesterol, are consistent and characteristic features of atherosclerotic lesions there is no indication that hypercholesterolemia plays more than a contributory role in their production” (1Peters J.P. VanSlyke D.D. Quantitative Clinical Chemistry. Williams 41: 723-728Google Scholar). However, very few practitioners paid much attention to cholesterol levels, dietary advice was minimal, and drug treatment for hypercholesterolemia was in its infancy. The evidence for the lipid hypothesis became stronger every year, but the idea that the cholesterol level could be centrally important was rejected, at times quite angrily, by many cardiologists and nutrition experts. In 1976, an editorial in the British Heart Journal concluded that: “The view that raised plasma cholesterol is per se a cause of coronary heart disease is untenable.” Sir John McMichael, then the preeminent British cardiologist, attacked the hypothesis in a 1979 article aggressively titled “Fats and Atheroma: An Inquest” (3McMichael J. Fats and atheroma—an inquest.BMJ. 1979; 1: 173-175Google Scholar). Even E. H. Ahrens, Jr., whose own pioneering clinical research showed conclusively that blood cholesterol could indeed be reduced by appropriate changes in diet, took strong exception to proposals to change the diet of the American public. In 1979, he wrote that such recommendations would be “unwise, impractical, and unlikely to lead to a reduced incidence of arteriosclerotic disease” (4Ahrens E.H. Dietary fats and coronary heart disease: unfinished business.Lancet. 1979; 2: 1345-1348Google Scholar). Michael Oliver, for many years a vocal skeptic regarding the importance of blood cholesterol levels, wrote in 1981: “It is probably of little value to reduce raised serum cholesterol concentrations in patients with overt coronary heart disease ” (5Oliver M.F. Lipid lowering and ischaemic heart disease.Acta Med. Scand. 1981; 651: 285-293Google Scholar). He also was on record to the effect that “reduction of raised serum cholesterol is a card of uncertain quality in the primary prevention of coronary heart disease” and that “reduction of raised serum cholesterol could lead to adverse biological changes” (6Oliver M.F. Serum-cholesterol the knave of hearts and the joker.Lancet. 1981; 2: 1090-1095Google Scholar). A letter to one of the British health-news newspapers referred to Oliver as one of the “Abominable No-men,” and an editorial comment in the Journal of the American College of Cardiology took issue with Oliver’s negative views and titled the essay “The Cholesterol Pessimist” (7Henry P.D. The cholesterol pessimist.J. Am. Coll. Cardiol. 1988; 12: 818-819Google Scholar). But Oliver’s skepticism was shared by many others. I. D. Frantz, Jr., and Richard B. Moore summarized the situation very aptly in 1969: “Few controversies have divided the medical community so sharply for such a long time as has the sterol hypothesis. The separation between the two points of view has become so extreme that, on the one hand, there are respected scientists who believe that the evidence is already so convincing that further clinical testing is unnecessary, financially wasteful and actually unethical; and, aligned against them, are equally respected scientists who believe that the total weight of evidence accumulated over the many years is too slight to justify further work along these lines” (8Frantz Jr., I.D. Moore R.B. The sterol hypothesis in atherogenesis.Am. J. Med. 1969; 46: 684-690Google Scholar). Sad to say, this was still the case in 1983, 15 years later, despite an ever-increasing number of epidemiologic studies, experimental animal studies, and additional intervention studies indicating a causal relationship between blood cholesterol and coronary heart disease. So, in 1983, we still needed a “you-can’t-argue-with-this” type of study, a blockbuster. That was finally provided by the large trial of cholesterol lowering sponsored by the National Institutes of Health (NIH) and published in 1984: the Coronary Primary Prevention Trial. For the first time, we had a large, randomized, double-blind study showing a statistically significant decrease in hard cardiovascular end points as a result of decreasing cholesterol level with the use of a bile acid binding resin, cholestyramine. With those data in hand, the NIH then convened a Consensus Conference to advise on whether decreasing blood cholesterol should become a national therapeutic goal (9Consensus Conference Lowering blood cholesterol to prevent heart disease.J. Am. Med. Assoc. 1985; 253: 2080-2086Google Scholar). The expert that the accumulated and trial data the not most the of the A lead article in the Medical Journal of by titled “The Lipid “The has a new and to the dietary and of The lipid hypothesis is J. Scholar). it this way: disease of the Coronary disease of the cholesterol Med. Scholar). a expert in lipid to cholesterol to cholesterol J. Med. Scholar). However, the Consensus Conference were at the time, and for a number of years by a small but vocal of For of at College of had this to about the of the have about this which the study that lowering cholesterol the of coronary disease. have the data to the “The at NIH have to this trial in the the people an Coronary heart the 1985; Scholar). Oliver had this to who the idea [of the Consensus were to use the for The of was to include who that levels of blood cholesterol in the are too high and should be this is was M.F. Consensus on coronary heart 1985; 1: Scholar). E. H. Ahrens, Jr., whose pioneering work had the important of diet on blood cholesterol levels, wrote in The “The in E.H. The in it been 1985; 1: Scholar). In its The published and on its a by J. Moore “The Cholesterol The cholesterol Scholar). a science “the have been by the on not by the heart but by a that a medical of the This the the heart National and and the American Heart Moore then on to very in the lipid at the time who had to to about the statins, which had been by for clinical use John I. and a series of about this of and the that “It is that one these physicians to such an is that their were in research by he is no to doubt the and of any of these the cholesterol controversy has its of This controversy over the years made it an uphill battle to the cardiologists especially the to attention to the statins, of cholesterol with in decreasing cholesterol levels, became in the and treatment of hypercholesterolemia become good medical Even Oliver finally accepted the hypothesis and to for treatment M.F. prevent coronary heart Scholar). In this series of I the cholesterol I that the importance of blood cholesterol levels in atherosclerosis should have and could have been much I point the that were the that because of and, most the on the of some to not the of clinical trials but the of the Today, we that we are the against coronary disease. can be In fact, clinical trials with the have in coronary heart disease and also total by is to lower coronary heart disease by and that is the result of years of to and treatment is in and not for years but for The history of this medical is worth for its own it is worth telling because we can to the mistakes of the and avoid in the future. 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